Craniomaxillofacial (CMF) surgery is required to address congenital birth defects and traumatic injuries to the face and jaw. CMF reconstruction is one of the most challenging areas for bone regeneration, as it requires modulated repair that leads to tissue regeneration while maintaining or recapitulating facial structure. Moreover, these facial bone reconstructions often suffer from bacterial infections that stall the healing process. Many different polymeric scaffold materials that exhibit degradability and minimal toxicity have been developed as bone void fillers to promote tissue regeneration in large CMF bone defects, but in general these materials do not intrinsically promote new bone growth or protect against infection. To this end, polymeric scaffold implants coated with electrostatic layer-by-layer (LbL) assemblies of polyelectrolyte polymers, pro-healing growth factor proteins, and antibiotics that can enhance bone regeneration have been developed. However, current polyelectrolyte- based constructs are engineered to degrade by non-specific hydrolysis and are minimally-responsive to the rate of tissue repair and bone regeneration or bacterial infection. Consequently, there is a need for LbL systems that better deliver therapies over the entire lifetime of the bone healing process and can respond to differential healing rates and flare-ups of bacterial infection. This project seeks to develop biomaterial implants coated with drug-loaded, environmentally-responsive LbL nanofilms that will selectively release drug payloads to generate a more robust healing response in infected, critically-sized CMF bone defects. Cell-responsive constructs can selectively release pro-healing therapeutics in response to new tissue growth or infection, thus creating a material scaffold system that can deliver reparative drugs ?on-demand?. It is predicted that more specifically controlling the release of therapeutic molecules from implanted materials will prolong the effective drug delivery window by conserving the drug only until it is needed, thereby increasing the relative efficiency of the treatment in vivo. Therefore, LbL coatings that are specifically degraded by cell-generated reactive oxygen species (ROS) and matrix metalloproteinase (MMP) enzymes, signals both associated with bone healing, will be created to specifically release pro-healing growth factors to improve the healing of CMF injuries. Once these responsive growth factor release systems are optimized, they will be combined with antibiotic-containing LbL coatings that selectively release their drug payload in response to bacterial infection. This work is anticipated to establish an effective platform for promoting cell-mediated drug delivery in LbL systems and has the potential to improve treatment outcomes in both CMF repair and across a variety of applications in regenerative medicine.